Abstract New therapeutics are needed for infections caused by the intestinal parasite Giardia. Current approved drugs have limiting toxicity and are ineffective dur to resistance in up to 20% of cases. We have identified a set of protein kinases in the Giardia genome that share an unusual structure feature in their active site. This feature, an atypically small gatekeeper residue, confers sensitivity to a class of compounds called bumped kinase inhibitors (BKI) that do not inhibit mammalian kinases. BKIs in general show good pharmacological properties and have shown minimal toxicity in mice when administered in the course of other work. We have demonstrated in preliminary work that even incomplete knockdown of these small-gatekeeper kinases significantly impairs Giardia growth. We have also shown that BKIs are active against Giardia in culture. We will use genetic and chemical probes to rigorously validate these kinases as drug targets. We will confirm that BKIs found to be active in suppressing Giardia growth, cell attachment, or encystation act by inhibiting specific kinases. A primary goal is to use SAR-guided synthetic chemistry to develop compounds that are orally bioavailable, sufficiently potent, lack toxicity, and cure animal models of Giardia infection. By the end of this project we expect to have lead compounds for evaluation as potential drugs against giardiasis.